Pain is a major public health issue, affecting a third of Americans. Loss of function as the result of pain costs our healthcare system over 300 billion dollars annually. Pain is a common morbidity after surgery, and most pain patients suffer from depressed mood (Scott, et al., J. Bone Joint Surg Br 2010; 92: 1253-8; Edwards, et al., Pain Res Manag 2009; 14: 307-11 Dworkin, et al., Clin J. Pain 1991; 7: 79-94; Romano et al., Psychol Bull 1985; 97: 18-34 and Rieckmann, et al., Psychother Pschother Psychosom 2006; 75: 353-61). Pain-induced depression impairs rehabilitation and worsens surgical outcome.
Depression is also a common and debilitating affective feature of chronic pain (Dworkin, et al., Clin J Pain 1991; 7: 79-94; Miller, et al., J Pain 2009; 10: 619-627). Current analgesics focus on sensory pain symptoms, but drugs such as NSAIDs and opioids have significant side effects. Thus, better understanding of the regulation of depression in pain states will result in new treatments that focus on the depressive symptoms of pain to improve daily function. It was previously shown that chronic neuropathic pain directly induces depression-like behavior (Wang, et al., Anesthesiology 2011; 115: 812-821). The circuit and synaptic mechanisms for the affective expression of pain, however, remain unknown. The nucleus accumbens (NAc), traditionally thought as an integral element in the brain reward circuitry that processes appetitive stimuli, has recently been shown by human imaging and animal studies to be activated by pain and other aversive stimuli (Becerra, et al., Eur J Pain 2008; 12: 866-869; Geha, et al. Neuron 2008; 60: 570-581; Gear, et al., Journal of Neuroscience 1999; 19: 7175-7181; Lammel, et al., Neuron 2011; 70: 855-862; Roitman, et al., Neuron 2005; 45: 587-597; and Reynolds, et al., Nat Neurosci 2008: 11: 423-425). The role of the NAc in depression is also emerging (Nestler, et al., Biol Psychiatry 2006; 59: 1151-9; Tokita, et al., Pharmacol Biochem Behav 2011; and Park, et al., Cell 2005; 122: 275-87). Because of the critical function NAc serves in mediating hedonic and motivational behaviors (Kable, et al., Neuron 2009; 63: 733-745; Fields, Reg Anesth Pain Med 2007; 32: 242-246), its role as a potential link between pain and depression was examined. Glutamate signaling which plays an important role in depression (Sanacora, et al., Neuropharmacology 2012; 62: 63-77) has been poorly studied in the NAc in aversive states.
The nucleus accumbens (NAc) is a strong candidate brain region for regulating depression in postoperative and chronic pain states. Most neurons in the NAc are medium spiny neurons (MSNs), which express dopamine and glutamate receptors. Dopamine signaling has been shown to provide descending pain inhibition by the midbrain-spinal cord pathway (Gear, et al J. Neurosci 1999; 19: 7175-81; Wood, Pain 2006; 120: 230-4). Glutamate signaling in the NAc is poorly studied in pain states, but it features prominently in depression studies (Sanacora, et al., Neuropharmacology 2011; Tokita, et al., Pharmacol Biochem Behav 2011; Koike, et al., Behav Brain Res 2011; 224: 107-11).
A key glutamate signaling mechanism is the trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (Ziff, Neuron 2007; 53: 627-33). AMPA receptors bind glutamate to conduct excitatory post-synaptic currents, and they are tetramers formed by varying combinations of four subunits, GluA1, 2, 3 and 4. GluA1 and GluA2 are the most abundant subunits in the NAc. GluA2-lacking AMPA receptors form in the NAc when GluA1 expression is increased, and they are permeable to calcium (Greger, et al Trends Neurosci 2007; 30: 407-16). These calcium permeable AMPA receptors (CPARs) can regulate calcium-dependent synaptic plasticity. While GluA2 subunits constitutively traffic to synapses, GluA1 trafficking is activity-dependent and hence may respond to rewards (Barry, et al. Curr Opin Neurobiol 2002; 12: 279-86) or pain. Thus, tightly controlled GluA1 trafficking promotes the formation of CPARs in the NAc and provides synaptic plasticity to regulate behaviors (Conrad, et al., Nature 2008; 454: 118-21). GluA1 has been shown to modulate depressive symptoms. For example, GluA1 knockout mice display vulnerability to depression (Chourbaji, et al., FASEB J 2008; 22: 3129-34), and decreased GluA1 levels in the NAc have been reported in rats that exhibit depressive behavior (Toth, et al., J. Neurochem 2008; 107: 522-32), whereas increased GluA1 levels are found in the NAc with antidepressant treatments (Tan, et al. Exp Brain Res 2006; 170: 448-56). Studies in chronic pain or postoperative pain, however, have not examined the role of GluA1 in the NAc, and our study seeks to address this knowledge gap.
Glutamatergic AMPA (α amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors mediate the majority of fast excitatory synaptic transmission in the brain. In the forebrain areas, AMPA receptors are heteromeric complexes assembled from mainly GluA1 and GluA2. The other two subunits of AMPA receptor, GluA3 and GluA4 express at relative lower levels. According to the new subunit nomenclature recommended by the International Union of Basic and Clinical Pharmacology (IUPHAR), these AMPA subunits are renamed as GluA1, GluA2, GluA3 and GluA4. Ampakines are a class of compounds known to enhance attention span and alertness, and facilitate learning and memory strongly interact with these receptors. Ampakines do not seem to have unpleasant, long-lasting side effects such as sleeplessness. They are currently being investigated as potential treatment for a range of conditions involving mental disability and disturbances such as Alzheimer's disease, Parkinson's disease, schizophrenia, Treatment-resistant depression (TRD) or neurological disorders such as Attention Deficit Hyperactivity Disorder (ADHD), among others. Ampakine activity has been established as one of the modes of action of the well established class of nootropics, the racetam drugs such as piracetam, aniracetam, oxiracetam and pramiracetam, however these drugs have multiple modes of action and produce only weak AMPA receptor activation. More recently developed ampakine compounds are much more potent and selective for the AMPA receptor target, and while none of the newer selective ampakine compounds have yet come onto the market, one compound CX717 is currently in Phase II clinical trials as of 2008. Four structural classes of ampakine drugs have been developed so far: the pyrrolidine derivative racetam drugs such as piracetam and aniracetam, the CX-series of drugs which encompass a range of benzoylpiperidine and benzoylpyrrolidine structures, benzothiazide derivatives such as cyclothiazide and IDRA-21, and biarylpropylsulfonamides such as LY-392,098, LY-404,187, LY-451,646 and LY-503,430. AMPAkines, however, have not been investigated in pain.